2-(4-piperidinyl)-1H-pyrido[4,3-b]-indol-1-ones and related compounds

ABSTRACT

A compound of the formula ##STR1## wherein R 1  is hydrogen, loweralkyl, phenyl, phenyl substituted by one or more loweralkyl, loweralkoxy, halogen, or trifluoromethyl groups, phenylloweralkyl or phenylloweralkyl in which the phenyl group is substituted by one or more loweralkyl, loweralkoxy, halogen, or trifluoromethyl groups; R 2  is loweralkyl, furanylloweralkyl, thienylloweralkyl, pyrrolylloweralkyl, pyridinylloweralkyl, phenylloweralkyl, or phenylloweralkyl in which the phenyl group is substituted by one or more loweralkyl, loweralkoxy, halogen, or trifluoromethyl groups; X is hydrogen, loweralkyl, loweralkoxy, halogen, or trifluoromethyl; m is 0 or 1; n is 1 or 2; an optical isomer thereof or a salt thereof.

This is a division of application Ser. No. 08/067,891 filed May 27,1993, U.S. Pat. No. 5,242,883 division of application Ser. No.07/821,364 filed Jan. 15, 1992U.S. Pat. No. 5,224,517 is a division ofapplication Ser. No. 07/588,870 filed Sep. 27, 1990 now U.S. Pat. No.5,102,889.

DESCRIPTION OF THE INVENTION

The present invention relates to novel 1H-pyrido[4,3-b]indol-1-ones.More particularly, the present invention relates to2-(4-piperidinyl)-1H-pyrido[4,3-b]indol-1-ones and related compounds offormula 1. ##STR2## wherein R¹ is hydrogen, loweralkyl, phenyl, phenylsubstituted by one or more loweralkyl, loweralkoxy, halogen, ortrifluoromethyl groups, phenylloweralkyl or phenylloweralkyl in whichthe phenyl group is substituted by one or more loweralkyl, loweralkoxy,halogen, or trifluoromethyl groups; R² is hydrogen, loweralkyl,furanylloweralkyl, thienylloweralkyl, pyrrolylloweralkyl,pyridinylloweralkyl, phenylloweralkyl, phenylloweralkyl in which thephenyl group is substituted by one or more loweralkyl, loweralkoxy,halogen, or trifluoromethyl groups, or a group of the formula ##STR3##wherein R³ is loweralkyl, haloloweralkyl, phenyl, phenyl substituted byone or more loweralkyl, loweralkoxy, halogen, or trifluoromethyl groups,phenylloweralkyl or phenylloweralkyl in which the phenyl group issubstituted by one or more loweralkyl, loweralkoxy, halogen, ortrifluoromethyl groups; X is hydrogen, loweralkyl, loweralkoxy, halogen,or trifluoromethyl; m is 0, 1, or 2; n is 1 or 2; or an optical isomerthereof, or a pharmaceutically acceptable salt thereof, which are usefulfor treating psychoses, alone or in combination with inert adjuvants.Preferred 2-(4-piperidinyl-1H-pyrido[4,3-b]indol-1-ones and relatedcompounds are those wherein R² is hydrogen, phenylloweralkyl orphenylloweralkyl in which the phenyl group is substituted by one or moreloweralkyl, loweralkoxy, halogen, or trifluoromethyl groups; and m is 1.

Subgeneric thereto are 1H-pyrido[4,3-b]indol-1-ones wherein R² is agroup of the formula ##STR4## wherein R³ is haloloweralkyl and m is 1.

The present invention also relates to indoles of formulas 2, 3, and 4##STR5## wherein R¹ is hydrogen, loweralkyl, phenyl, phenyl substitutedby one or more loweralkyl, loweralkoxy, halogen, or trifluoromethylgroups, phenylloweralkyl or phenylloweralkyl in which the phenyl groupis substituted by one or more loweralkyl, loweralkoxy, halogen, ortrifluoromethyl groups; R² is loweralkyl, furanylloweralkyl,thienylloweralkyl, pyrrolylloweralkyl, pyridinylloweralkyl,phenylloweralkyl, or phenylloweralkyl in which the phenyl group issubstituted by one or more loweralkyl, loweralkoxy, halogen, ortrifluoromethyl groups; X is hydrogen, loweralkyl, loweralkoxy, halogen,or trifluoromethyl; m is 0, 1 or 2; n is 1 or 2; or an optical isomerthereof, or a salt thereof, which are useful as intermediates for thesynthesis of the ultimate 2-(4-piperidinyl)-1H-pyrido[4,3-b]indol-1-onesand related compounds of formula 1.

Preferred intermediates 2, 3, and 4 are those wherein R² isphenylloweralkyl; and m is 1.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 7 carbon atoms such asmethyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl,4-heptyl and the like; the term "alkoxy" refers to a monovalentsubstituent which consists of an alkyl group linked through an etheroxygen and having its free valence bond from the ether oxygen such asmethoxy, ethoxy, propoxy, butoxy, 1,1-dimethylethoxy, pentoxy,3-methylpentoxy, 2-ethylpentoxy and the like; the term "halogen" refersto a member of a family consisting of chlorine, fluorine, bromine oriodine. The term "lower" as applied to any of the aforementioned groupsrefers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by the synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof. The formulas of the compounds shown herein are intended toencompass all possible optical isomers of the compounds so depicted.

The novel 2-(4-piperidinyl)-1H-pyrido[4,3-b]indol-1-ones and relatedcompounds of the present invention are prepared by condensing apyrano[4,3-b]indol-1,3-dione 5, the preparation of which is described inG. A. Bahadur, et al., Journal Chemical Society Perkin I, 1688 (1980),with an amine of formula 11 ##STR6## wherein R² is loweralkyl,furanylloweralkyl, thienylloweralkyl, pyrrolylloweralkyl,pyridinylloweralkyl, phenylloweralkyl, or phenylloweralkyl in which thephenyl group is substituted by one or more loweralkyl, loweralkoxy,halogen, or trifluoromethyl groups and m is as defined above to anindoleacetamidocarboxylic acid 6, which is decarboxylated to anindoleacetamide 7, and, in turn, reduced to an indolylethanamine 8andcyclized to an indolone 1.

The condensation is conveniently performed by contacting a pyranoindole5 with an amine 11 in a solvent, for example, an alkanol such asmethanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol, ethanolbeing preferred. The condensation temperature is not critical. It ispreferred, however, to perform the condensation at the refluxtemperature of the reaction medium to assure a reasonable rate of ringopening.

The decarboxylation of an indolecarboxylic acid 6 to an indoleacetamide7 is accomplished by heating the carboxylic acid 6 to its melting pointand maintaining the melt at this temperature until the evolution ofcarbon dioxide ceases.

The reduction of an indoleacetamide 7 to an indoleethanamine 8 iseffected by treating an acetamide 7 with a complex metal hydride in anethereal solvent. Among complex metal hydrides are alkali metal aluminumhydrides such as lithium aluminum hydride and sodium aluminum hydride.Among ethereal solvents are diethyl ether, 1,2-dimethyoxyethane,2-methoxyethyl ether, tetrahydrofuran, and dioxane, and combinationsthereof. A reduction promoter, for example, an aluminum trihalide suchas aluminum trichloride may be employed to facilitate the reaction. Thepreferred reduction medium consists of lithium aluminum hydride intetrahydrofuran/ether containing aluminum chloride. The initial phase ofthe reduction, i.e., the mixing of the acetamide 7, complex metalhydride, and reduction promoter is preferably performed at a reducedtemperature of about 0° C. The reduction is completed at about 25° C.

The cyclization of an indoleethanamine 8 to a1H-pyrido[4,3-b]indol-1-one 1 is achieved by treating an ethanamine 8with a compound of the formula ##STR7## wherein Hal is chloro or bromoin a suitable solvent at a temperature within a noncritical temperaturerange of about 0° C. to about 50° C., a temperature of about 25° C.being preferred. Among suitable solvents there may be mentioned aromaticsolvents, for example, benzene, and toluene, and halocarbons, forexample, dichloromethane, trichloromethane, and 1,1- and1,2-dichloroethane, and combinations thereof. Phosgene, i.e., a compoundof formula 12 wherein Hal is chloro is the preferred cyclizing agent. Acombination of aromatic and halocarbon solvents is preferred. Acombination of toluene and dichloromethane is most preferred. To preparea 1H-pyrido[4,3-b]indol-1-one of formula 10, i.e., an indolone offormula 1 wherein R² is hydrogen, an indolone 1 wherein R² isphenylmethyl or substituted phenylmethyl is acylated to anN-haloalkoxycarbonylpiperidinylindolone 9 wherein R³ is haloloweralkyland R¹, X, m, and n are as hereinbefore described, which is cleaved to10.

The acylation is carded out by contacting indolone 1 (R² is phenylmethylor substituted phenylmethyl) with a haloloweralkylhaloformate of formula13 ##STR8## wherein R³ is haloloweralkyl and Hal is chloro or bromo in ahalocarbon such as dichloromethane, trichloromethane, or 1,1-dichloro-or 1,2-dichloroethane, preferably at the reflux temperature of thereaction medium. 1,2-Dichloroethane is the preferred solvent.

The cleavage of a haloloweralkoxycarbonylpiperidinylindolone 9 to apiperidinylindolone 10 is conducted in an alkanol such as methanol,ethanol, 1- or 2-propanol, or 1,1-dimethylethanol, methanol beingpreferred, at a temperature from about 25° C. to the reflux temperatureof the reaction medium, the reflux temperature being preferred.

While the synthesis of the compounds of the present invention isdescribed for the piperidinyl derivatives (wherein m is 1 ), thepyrrolidinyl (wherein m is 0) and azepinyl (wherein m is 2) derivativesmay be prepared by substantially similar processes.

The 2-(4-piperidinyl)-1H-pyrido[4,3-b]indol-1-ones and related compoundsof the present invention are useful for treating psychoses by vitue oftheir ability to elicit an antipsychotic response in mammals.

Antipsychotic activity is determined in the climbing mice assay bymethods similar to those described by P. Protais et al.,Psychopharmacol., 50, 1(1976) and B. Costall, Eur. J. Pharmacol., 50,39(1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4" by 10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally 30 minutes prior to the apomorphine challengeat a screening dose of 10 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior     Score                                                   ______________________________________                                        Mice with:                                                                    4 paws on bottom (no climbing)                                                                      0                                                       2 paws on the wall (rearing)                                                                        1                                                       4 paws on the wall (full climb)                                                                     2                                                       ______________________________________                                    

Mice consistently climbing before the injection of apormorphine arediscarded.

With full-developed apomorphine climbing, the animals are hanging ontothe cage wails, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score; 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitioneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits are calculated by a linear regressionanalysis. Antipsychotic activity expressed as the ED₅₀ value ofrepresentative 2-(4-piperidinyl)-1H-pyrido[4,3-b]indolones and relatedcompounds as well as two standard antipsychotics are presented in TableI.

                  TABLE I                                                         ______________________________________                                                         Antipsychotic Activity                                       Compound         ED.sub.50 (mg/kg, ip)                                        ______________________________________                                        5-methyl-2-[1-(phenyl-                                                                         4.6                                                          methyl)-4-piperidinyl]-                                                       2,3,4,5-tetrahydro-1H-                                                        pyrido[4,3-b]indol-1-one                                                      haloperidol (standard)                                                                         0.14                                                         thioridazine     3.6                                                          ______________________________________                                    

Antipsychotic activity is achieved when the present2-(4-piperidinyl)-1H-pyrido[4,3-b]indolones and related compounds areadministered to a subject requiring such treatment as effective oral,parenteral or intravenous dose of from 0.0 1 to 50 mg/kg of body weightper day. A particularly preferred effective range is about 1 to 5 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjusted to theindividual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Antagonism of apomorphine-induced stereotypy is a property of manyantipsychotics. Antipsychotics displaying little effect in this assaywould be expected to show a low propensity to cause undesirableextrapyramidal side effects and/or tardive dyskinesias in mammals.Antagonism of apomorphine-induced stereotypy of the present2-(4-piperidinyl)-1H-pyrido[4,3-b]indol-1-ones is determined by methodssimilar to those described by N. E. Anden, et al., J. Pharma.Pharmacol., 19, 627, (1967) and A. M. Ernst, et al., Psychopharmacologia(Bed.), 10, 316, (1967).

Groups of male Wistar rats (125-200 grams) are used and food and waterare available ad libitum. Drugs are prepared using distilled water and,if insoluble, a suitable surfactant is added. The route ofadministration may be varied and the dosage volume is 10 ml/kg. For aprimary screen, a group size of six is used. Drug is administered onehour prior to scoring and the animals are placed in individual clearplastic cages (24×14×13 cm). The control group receives vehicle.Apomorphine hydrochloride solution is prepared at a concentration of 1.5mg/10 ml in a 0.03% ascorbic acid stock solution (30 mg of ascorbic acidin 100 ml of 1% saline) to increase the stability of the apomorphinehydrochloride while in solution. Apomorphine hydrochloride solution isadministered at a dose of 1.5 mg/kg subcutaneous (s.c.) with a dosagevolume of 1 ml/kg. Fifty minutes after drug dosing, stereotypic behavioris noted. Stereotypic activity is defined as sniffing, licking orchewing behavior that occurs in a repetitive manner and is rated asfollows: Constant sniffing, licking or chewing without interruption; theanimal is considered protected if this behavior is interrupted.

The percent effectiveness of a drug is determined by the number ofanimals protected in each group.

A dose-response is run in the same manner as a primary screen exceptthat a group size of 10 is used and the animals are dosed in arandomized manner. One group receives vehicle. ED₅₀ for stereotypy arecalculated by means of probit analysis.

Inhibition of apomorphine-induced stereotypy by a representative2-(4-piperidinyl)-1H-pyrido[4,3-b]indolone of the present invention andtwo standards is given in Table II.

                  TABLE II                                                        ______________________________________                                                         Dose      % Inhibition                                                        (mg/kg, ip)                                                                             of Apomorphine-                                    Compounds        body wt.) Induced Stereotypy                                 ______________________________________                                        5-methyl-2-[1-(phenylmethyl)-                                                                  24        50                                                 4-piperidinyl]-2,3,4,5-tetra-                                                 hydro-1H-pyrido[4,3-b]indol-                                                  1-one                                                                         haloperidol      0.2       50                                                 thioridazine     38        50                                                 ______________________________________                                    

Compounds of the invention include:

a.8-ethyl-5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

b.7-ethoxy-5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

c.7,8-dichloro-5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

d.6-bromo-5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

e.5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-9-trifluoromethyl-1H-pyrido[4,3-b]indol-1-one;

f.5-methyl-2-[1-phenylmethyl)-3-pyrrolidinyl]-2,3,4,5-tetrahdyro-1H-pyrido[4,3-b]indol-1-one;

g.5-methyl-2-[1-(phenylmethyl)-4-(2,3,4,5,6,7-hexahydroazepinyl)]-2,3,4,5-tetrahydro-1H-pyrido-[4,3-b]indol-1-one;

h.5-methyl-2-[1-(4-ethylphenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

i.5-methyl-2-[1-(4-ethoxyphenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

j.5-methyl-2-[1-(5-chlorophenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

k.5-methyl-2-[1-(3,4-dichlorophenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

l. 1.5-methyl-2-[1-(4-trifluoromethylphenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

m.5-methyl-2-(4-piperidinyl)-2,3,4,5-tetrahyro-1H-pyrido[4,3-b]indol-1-one;

n.5-methyl-2-(1-methyl-4-piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

o. 2-(4-piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1H-one;

p.5-phenyl-2-(4-piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

q.2-(4-piperidinyl)-5-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

r.2-(4-piperidinyl)-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;s.2-(4-piperidinyl)-5-(3-methoxyphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

t.5-(4-trifluoromethyl)-2-(piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

u.5-(phenylethyl)-2-(piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

v.5-[(2-chlorophenyl)methyl]-2-(piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

w.5-[(4-methylphenyl)methyl]-2-(piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

x.5-[(3-methoxyphenyl)methyl]-2-(piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

y.2-(piperidinyl)-5-[(3-trifluoromethyl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;p0 z.5-methyl-2-[1-(2-furanylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

a'.5-methyl-2-[1-(3-thienylmethyl)-4-piperidinyl]-2,3,4,5,-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

b'.5-methyl-2-[1-(2-pyrrolylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

c'.5-methyl-2-[1-(3-pyridinylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

d'.2-[1-(methylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

e'.2-[1-(phenylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

f'.2-[1-(2-chlorophenylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

'.2-[1-(2-methylphenylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

h'.2-[1-(2-methoxyphenylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one;

i'.5-methyl-2,3,4,5-tetrahydro-2-[1-(3-trifluoromethylphenylcarbamoyl)-1H-pyrido[4,3-b]indol-1-one;

j'. 1H-indole-2-[N-(phenylmethyl-4-piperidinyl)acetamido]-3-carboxylicacid;

k'. 1H-indole-2-[N-(phenylmethyl-4-piperidinyl)-acetamido]-3-carboxylicacid;

l'.2-(1-methyl-1H-indol-2-yl)-N-[1-(2-methylphenyl)-methyl-4-piperidinyl]ethanamine;

m'.N-[1-(4-methoxyphenyl)methyl-4-piperidinyl]-2-(1-methyl-1H-indol-2-yl)ethanamine;

n'.N-[1-(2-bromophenyl)methyl-4-piperidinyl]-2-(1-methyl-1H-indol-2-yl)ethanamine;

o'.2-(1-methyl-1H-indol-2-yl)-N-[1-(3-trifluoromethylphenyl)methyl-4-piperidinyl]ethanamine;

p'.2-[N-[1-(2-furanyl)methyl]-4-piperidinylacetamido]-1H-indole-1-methyl-3-carboxylicacid;

q'.1H-indole-1-methyl-2-[N-[1-(3-thienyl)methyl]-4-piperidinyl]acetamide;

r'.2-[N-[1-(2-pyrrolyl)methyl]-4-piperidinyl]1-H1-indole-1-methylacetamide;and

s'.2-(1-methyl-1H-indol-2-yl-N-[1-[3-(pyridinyl)-methyl-4-piperidinyl)]ethanamine.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0. 1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodiumbisulifite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, titrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1

1H-Indole-1-methyl-2-[N-(phenylmethyl-4-piperidinyl)acetamido]-3-carboxylicacid

A solution of 4,5-dihydro-5-methylpyrano[4,3-b]indole-1,3-dione (9.95g), 4-amino-1-phenylmethylpiperidine (10.55 g), and 95% ethanol (200 ml)was heated under reflux overnight, with stirring. The solution wasevaporated and the residue was dissolved in dichloromethane (200 ml).The solution was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by high performanceliquid chromatography (silica gel, eluted with20%-methanol/dichloromethane). The appropriate fractions were collected,combined, and evaporated. A 5.0 g-portion of the residue wasrecrystallized from hot methanol to yield 4.4 g (61% ) of product, mp147°-9° C. (dec).

ANALYSIS: Calculated for C₂₄ H₂₇ N₃₀ O₃ : 71.09% C 6.71% H 10.36% NFound: 71.22% C 6.83% H 10.37% N

EXAMPLE 2

1H-Indole-1-methyl-2-[N-(1-phenylmethyl-4-piperidinyl)]acetamide

1H-Indole-1-methyl-2-[N-(1-phenylmethyl-4-piperidinyl)acetamido]-3-carboxylicacid (6.66 g) was melted and held at 60° C. for one-half hour, until gasevolution ceased. The melt was purified by high performance liquidchromatography (silica gel, eluted with 10%-methanol/dichloromethane).The appropriate fractions were collected, combined, and evaporated toyield 4.50 g (76%) of product, mp 207°-8° C.

ANALYSIS: Calculated for C₂₃ H₂₇ N₃ O: 76.42% C 7.53% H 11.62% N Found:76.14% C 7.46% H 11.59% N

EXAMPLE 3

2-(1-Methyl-1H-indol-2-yl)-N-(1-phenylmethyl-4-piperidinyl)ethanamine

To a solution of lithium aluminum hydride (1M in tetrahydrofuran, 63 ml)and ether (120 ml) was added over 10 rains aluminum trichloride (8.4 g)at 0° C., under nitrogen, with stirring. The mixture was stirred for 15rains at 0° C. and1H-indol-1-methyl-2-[N-(1-phenylmethyl-4-piperidinyl)]acetamide wasadded. The mixture was stirred at room temperature for 1.5 hrs and wasquenched with 1N aqueous sodium hydroxide solution (500 ml), added over20 mins. The aqueous phase was extracted with dichloromethane (3×250ml), and the combined organic phase was washed with water (500 ml),brine (500 ml), dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by high performanceliquid chromatography (silica gel, 50% methanol/dichloromethane). Theappropriate fractions were collected, combined, and evaporated. Theresidue solidified upon standing. The solid was recrystallized from hothexane to give 5.9 g of product, mp 72°-73° C.

ANALYSIS: Calculated for C₂₃ H₂₉ N₃ : 79.50% C 8.41% H 12.09% N Found:79.68% C 8.66% H 12.12% N

EXAMPLE 4

5-Methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole-1-onehydrochloride

To a solution of phosgene (1.93M in toluene, 3.58 ml) anddichloromethane (25 ml) was added a solution of2-(1-methyl-1H-indol-2-yl)-N-(1-phenylmethyl4-piperidinyl)ethanamine(0.80 g) and dichloromethane (25 ml), with stirring. The mixture wasstirred overnight, quenched with water, and basified with sodiumhydroxide solution. The phases were separated. The organic phase waswashed with water, brine, dried over anhydrous sodium sulfate, filtered,and the filtrate was evaporated. The residue was combined with theresidue from a second experiment and purified by high performance liquidchromatography (silica gel column, eluted with 7.5%methanol/dichloromethane). The appropriate fractions were collected,combined, and evaporated to yield 1.25 g (20%) of product, mp 191°-3°C., as the free base.

A solution of the free base and methanol (10 ml) was treated withethereal hydrogen chloride and diluted with ether. The precipitate wascollected, dried, and recrystallized from 1-propanol to afford product,mp 302°-305° C. (dec).

ANALYSIS: Calculated for C₂₄ H₂₇ N₃ O.HCl: 70.32% C 6.88% H 10.25% NFound: 70.11% C 6.94% H 10.08% N

EXAMPLE 5

2-[1-(α-Chloroethylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

To a solution of5-methyl-2-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3,-b]indol-1-one(0.40 g) in dichloromethane (4.0 ml) was added α-chloroethylchloroformate (0.16 ml) at 0° C., with stirring. The solution was heatedunder reflux for 3 hrs, under nitrogen, and then stirred at roomtemperature for 1 hr. The reaction mixture was evaporated under reducedpressure. The residue was dissolved in dichloromethane and washedsequentially with brine, 10% sodium hydroxide solution, and brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica gel, 5% methanol/ethyl acetate). The appropriatefractions were collected, combined, and concentrated to yield 0.30 g(70%) of product.

EXAMPLE 6

5-Methyl-2-(4-piperidinyl)-2,3,4,5-tetrahydro-1H-pyrido-[4,3-b]indol-1-onedihydrochloride monohydrate

2-[1-(α-Chloroethylcarbamoyl)-4-piperidinyl]-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one(0.300 g) was dissolved in anhydrous methanol (6 ml), and the solutionwas heated under reflux for 4 hrs. The reaction mixture was evaporated,and the residue was recrystallized from absolute ethanol to afford 0.10g (50% ) of product.

ANALYSIS: Calculated for C₁₇ H₂₁ N₃ O.2HCl.H₂ O: 54.56% C 6.73% H 11.23%N Found: 55.03% C 6.69% H 11.20% N ##STR9##

We claim:
 1. A compound of the formulawherein R¹ is hydrogen,loweralkyl, phenyl, phenyl substituted by one or more loweralkyl,loweralkoxy, halogen, or trifluoromethyl groups, phenylloweralkyl orphenylloweralkyl in which the phenyl group is substituted by one or moreloweralkyl, loweralkoxy, halogen, or trifluoromethyl groups; R² isloweralkyl, furanylloweralkyl, thienylloweralkyl, pyrrolylloweralkyl,pyridinylloweralkyl, phenylloweralkyl, or phenylloweralkyl in which thephenyl group is substituted by one or more loweralkyl, loweralkoxy,halogen, or trifluoromethyl groups; X is hydrogen, loweralkyl,loweralkoxy, halogen, or trifluoromethyl; m is 0, or 1; n is 1 or 2; anoptical isomer thereof or a salt thereof.
 2. A compound according toclaim 1 wherein R² is phenylloweralkyl; and m is
 1. 3. The compoundaccording to claim 2 which is2-(1-methyl-1H-indol-2-yl)-N-(1-phenylmethyl-4-piperidinyl)ethanamine.